tbuckley/cabot-search huggingface dataset:
Icosapent ethyl in cardiovascular prevention: Resolution of inflammation through the eicosapentaenoic acid - resolvin E1 - ChemR23 axis
Authors: Magnus Bäck
Journal: Pharmacology & Therapeutics (2023)

Cardiovascular outcome trials on omega-3 fatty acids have generated contradictory results but indicate a dose-dependent beneficial effect of eicosapentaenoic acid (EPA). Beneficial cardiovascular effects of EPA may in addition to triglyceride lowering be mediated through alternative mechanisms of action. In this review, the link between EPA and a resolution of atherosclerotic inflammation is addressed. EPA is a substrate for the enzymatic metabolism into the lipid mediator resolvin E1 (RvE1), which activates the receptor ChemR23 to transduce an active resolution of inflammation. This has been shown to dampen the immune response and provide atheroprotective responses in different models. The intermediate EPA metabolite 18-HEPE emerges as a biomarker of EPA metabolism towards proresolving mediators in observational studies. Genetic variations within the EPA-RvE1-ChemR23 axis affecting the response to EPA may open up for precision medicine to identify responders and non-responders to EPA and fish oil supplementation. In conclusion, activation of the EPA-RvE1-ChemR23 axis towards a resolution of inflammation may contribute to beneficial effects in cardiovascular prevention.
Glutamate-releasing BEST1 channel is a new target for neuroprotection against ischemic stroke with wide time window
Authors: Shuai Xiong, Hui Xiao, Meng Sun, Yunjie Liu, Ling Gao, Ke Xu, Haiying Liang, Nan Jiang, Yuhui Lin, Lei Chang, Haiyin Wu, Dongya Zhu, Chunxia Luo
Journal: Acta Pharmaceutica Sinica B (2023)

Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke. The narrow treatment time window is still to be solved. Given that the ischemic core expanded over days, treatment with an extended time window is anticipated. Bestrophin 1 (BEST1) belongs to a bestrophin family of calcium-activated chloride channels. We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice. Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits. Using electrophysiological recordings, we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity. Finally, we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6-72 h post-ischemia in rodents. This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions. Our study identifies the glutamate-releasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.
Impact of COVID-19 on broad-spectrum antibiotic prescribing for common infections in primary care in England: a time-series analyses using OpenSAFELY and effects of predictors including deprivation
Authors: Xiaomin Zhong, Alexander Pate, Ya-Ting Yang, Ali Fahmi, Darren M. Ashcroft, Ben Goldacre, Brian MacKenna, Amir Mehrkar, Sebastian CJ. Bacon, Jon Massey, Louis Fisher, Peter Inglesby, Kieran Hand, Tjeerd van Staa, Victoria Palin
Journal: The Lancet Regional Health - Europe (2023)

The COVID-19 pandemic impacted the healthcare systems, adding extra pressure to reduce antimicrobial resistance. Therefore, we aimed to evaluate changes in antibiotic prescription patterns after COVID-19 started.
The role of population-level preventive care for brain health in ageing
Authors: Behnam Sabayan, Sara Doyle, Natalia S Rost, Farzaneh A Sorond, Kamakshi Lakshminarayan, Lenore J Launer
Journal: The Lancet Healthy Longevity (2023)

Over the past several decades, a worldwide demographic transition has led to an increasing number of older adults with chronic neurological conditions. These conditions, which have a profound effect on the cognitive function and physical ability of older adults, also have a long preclinical phase. This feature provides a unique opportunity to implement preventive measures for high-risk groups and the population as a whole, and therefore to reduce the burden of neurological diseases. The concept of brain health has emerged as the overarching theme to define overall brain function independently of underlying pathophysiological processes. We review the concept of brain health from the ageing and preventive care perspectives, discuss the mechanisms underpinning ageing and brain ageing, highlight the interplay of various forces resulting in deviation from brain health towards brain disease, and provide an overview of strategies to promote brain health with a life-course approach.
A highly selective C-rhamnosyltransferase from Viola tricolor and insights into its mechanisms
Authors: Bo-Yun Han, Zi-Long Wang, Junhao Li, Qing Jin, Hao-Tian Wang, Kuan Chen, Yang Yi, Hans Ågren, Xue Qiao, Min Ye
Journal: Acta Pharmaceutica Sinica B (2023)

C-Glycosides are important natural products with various bioactivities. In plant biosynthetic pathways, the C-glycosylation step is usually catalyzed by C-glycosyltransferases (CGTs), and most of them prefer to accept uridine 5'-diphosphate glucose (UDP-Glc) as sugar donor. No CGTs favoring UDP-rhamnose (UDP-Rha) as sugar donor has been reported, thus far. Herein, we report the first selective C-rhamnosyltransferase VtCGTc from the medicinal plant Viola tricolor. VtCGTc could efficiently catalyze C-rhamnosylation of 2-hydroxynaringenin 3-C-glucoside, and exhibited high selectivity towards UDP-Rha. Mechanisms for the sugar donor selectivity of VtCGTc were investigated by molecular dynamics (MD) simulations and molecular mechanics with generalized Born and surface area solvation (MM/GBSA) binding free energy calculations. Val144 played a vital role in recognizing UDP-Rha, and the V144T mutant could efficiently utilize UDP-Glc. This work provides a new and efficient approach to prepare flavonoid C-rhamnosides such as violanthin and iso-violanthin.
Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions
Authors: Owen S. Skinner, Joan Blanco-Fernández, Russell P. Goodman, Akinori Kawakami, Hongying Shen, Lajos V. Kemény, Lena Joesch-Cohen, Matthew G. Rees, Jennifer A. Roth, David E. Fisher, Vamsi K. Mootha, Alexis A. Jourdain
Journal: Nature Metabolism (2023)

Abstract Glucose is vital for life, serving as both a source of energy and carbon building block for growth. When glucose is limiting, alternative nutrients must be harnessed. To identify mechanisms by which cells can tolerate complete loss of glucose, we performed nutrient-sensitized genome-wide genetic screens and a PRISM growth assay across 482 cancer cell lines. We report that catabolism of uridine from the medium enables the growth of cells in the complete absence of glucose. While previous studies have shown that uridine can be salvaged to support pyrimidine synthesis in the setting of mitochondrial oxidative phosphorylation deficiency 1 , our work demonstrates that the ribose moiety of uridine or RNA can be salvaged to fulfil energy requirements via a pathway based on: (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/UPP2 into uracil and ribose-1-phosphate (R1P), (2) the conversion of uridine-derived R1P into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway and (3) their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis. Capacity for glycolysis from uridine-derived ribose appears widespread, and we confirm its activity in cancer lineages, primary macrophages and mice in vivo. An interesting property of this pathway is that R1P enters downstream of the initial, highly regulated steps of glucose transport and upper glycolysis. We anticipate that ‘uridine bypass’ of upper glycolysis could be important in the context of disease and even exploited for therapeutic purposes.
Artificial intelligence, machine learning, and deep learning in liver transplantation
Authors: Mamatha Bhat, Madhumitha Rabindranath, Beatriz Sordi Chara, Douglas A. Simonetto
Journal: Journal of Hepatology (2023)

Liver transplantation (LT) is a life-saving treatment for individuals with end-stage liver disease. The management of LT recipients is complex, predominantly because of the need to consider demographic, clinical, laboratory, pathology, imaging, and omics data in the development of an appropriate treatment plan. Current methods to collate clinical information are susceptible to some degree of subjectivity; thus, clinical decision-making in LT could benefit from the data-driven approach offered by artificial intelligence (AI). Machine learning and deep learning could be applied in both the pre- and post-LT settings. Some examples of AI applications pre-transplant include optimising transplant candidacy decision-making and donor-recipient matching to reduce waitlist mortality and improve post-transplant outcomes. In the post-LT setting, AI could help guide the management of LT recipients, particularly by predicting patient and graft survival, along with identifying risk factors for disease recurrence and other associated complications. Although AI shows promise in medicine, there are limitations to its clinical deployment which include dataset imbalances for model training, data privacy issues, and a lack of available research practices to benchmark model performance in the real world. Overall, AI tools have the potential to enhance personalised clinical decision-making, especially in the context of liver transplant medicine.
Optimum fractionation of radiation to combine PD‐1 blockade
Authors: Feifei Teng, Tianwen Yin, Xiao Ju, Peiliang Wang, Yungang Wang, Jinming Yu
Journal: MedComm (2023)

Abstract The optimum fractionation of radiation to combine with immune checkpoint blockade is controversial. This study aimed to investigate the fractionated radiation to maximize immunity during combination therapy. To evaluate the abscopal effect, C57BL/6 hPD‐1 knock‐in mice bearing two syngeneic contralateral MC38 murine colon cancer tumors were treated with four distinct regimens of radiotherapy. Three fractions of 8 Gy were chosen as the optimal fractionation to combine with anti‐PD‐1 as the optimal fractionation for maximizing immunity. Anti‐PD‐1 administration enhanced both local and systemic antitumor immunity in a cytotoxic T cell–dependent manner. Meanwhile, the spleen exhibited decreased myeloid‐derived suppressor cells (MDSCs) under combination treatment. Furthermore, RNA‐sequencing revealed significantly increased tumor necrosis factor (TNF) receptors and cytokines associated with lymphocyte infiltration in the combining group. Here we demonstrate that the hypofractionation of 8 Gy × 3f was the optimum‐fractionated dosage to maximize immunity, and the combination of anti‐PD‐1 showed promising results in boosting abscopal effect. Underlying mechanisms may include the activation of T cells and the reduction of MDSCs, which is achieved through the action of TNF and related cytokines. This study indicates a radioimmunotherapy dosage painting method that can be developed to overcome present limitations in tumor immunosuppression.
The Effects of Low-Carbohydrate versus Conventional Weight Loss Diets in Severely Obese Adults: One-Year Follow-up of a Randomized Trial
Authors: Linda Stern, Nayyar Iqbal, Prakash Seshadri, Kathryn L. Chicano, Denise A. Daily, Joyce McGrory, Monica Williams, Edward J. Gracely, Frederick F. Samaha
Journal: Annals of Internal Medicine (2004)

Background: A previous paper reported the 6-month comparison of weight loss and metabolic changes in obese adults randomly assigned to either a low-carbohydrate diet or a conventional weight loss diet. Objective: To review the 1-year outcomes between these diets. Design: Randomized trial. Setting: Philadelphia Veterans Affairs Medical Center. Participants: 132 obese adults with a body mass index of 35 kg/m2 or greater; 83% had diabetes or the metabolic syndrome. Intervention: Participants received counseling to either restrict carbohydrate intake to <30 g per day (low-carbohydrate diet) or to restrict caloric intake by 500 calories per day with <30% of calories from fat (conventional diet). Measurements: Changes in weight, lipid levels, glycemic control, and insulin sensitivity. Results: By 1 year, mean (±SD) weight change for persons on the low-carbohydrate diet was −5.1 ± 8.7 kg compared with −3.1 ± 8.4 kg for persons on the conventional diet. Differences between groups were not significant (−1.9 kg [95% CI, −4.9 to 1.0 kg]; P = 0.20). For persons on the low-carbohydrate diet, triglyceride levels decreased more (P = 0.044) and high-density lipoprotein cholesterol levels decreased less (P = 0.025). As seen in the small group of persons with diabetes (n = 54) and after adjustment for covariates, hemoglobin A1c levels improved more for persons on the low-carbohydrate diet. These more favorable metabolic responses to a low-carbohydrate diet remained significant after adjustment for weight loss differences. Changes in other lipids or insulin sensitivity did not differ between groups. Limitations: These findings are limited by a high dropout rate (34%) and by suboptimal dietary adherence of the enrolled persons. Conclusion: Participants on a low-carbohydrate diet had more favorable overall outcomes at 1 year than did those on a conventional diet. Weight loss was similar between groups, but effects on atherogenic dyslipidemia and glycemic control were still more favorable with a low-carbohydrate diet after adjustment for differences in weight loss.
A 10-Year Prospective Study of Primary Hyperparathyroidism with or without Parathyroid Surgery
Authors: Shonni J. Silverberg, Elizabeth Shane, Thomas P. Jacobs, Ethel Siris, John P. Bilezikian
Journal: New England Journal of Medicine (1999)

In the United States, most patients with primary hyperparathyroidism have few or no symptoms. The need for parathyroidectomy to treat all patients with this disorder has therefore been questioned.
Lymph Node Ratio as an Alternative to pN Staging in Node-Positive Breast Cancer
Authors: Vincent Vinh-Hung, Helena M. Verkooijen, Gerald Fioretta, Isabelle Neyroud-Caspar, Elisabetta Rapiti, Georges Vlastos, Carole Deglise, Massimo Usel, Jean-Michel Lutz, Christine Bouchardy
Journal: Journal of Clinical Oncology (2009)

Purpose In the current pTNM classification system, nodal status of breast cancer is based on the number of involved lymph nodes and does not account for the total number of lymph nodes removed. In this study, we assessed the prognostic value of the lymph node ratio (LNR; ie, ratio of positive over excised lymph nodes) as compared with pN staging and determined its optimal cutoff points. Patients and Methods From the Geneva Cancer Registry, we identified all women diagnosed with node-positive breast cancer between 1980 and 2004 (n = 1,829). The prognostic value of LNRs was calculated for values ranging from 0.05 to 0.95 by Cox regression analysis and validated by bootstrapping. Based on maximum likelihood, we identified cutoff points classifying women into low-, intermediate-, and high-risk LNR groups. Results Optimal cutoff points classified patients into low- (≤ 0.20), intermediate- (&gt; 0.20 and ≤ 0.65), and high-risk (&gt; 0.65) LNR groups, corresponding to 10-year disease-specific survival rates of 75%, 63%, and 40%, and adjusted mortality risks of 1 (reference), 1.78 (95% CI, 1.46 to 2.18), and 3.21 (95% CI, 2.54 to 4.06), respectively. In contrast to LNR risk categories, survival curves of pN2 and pN3 crossed after 15 years, and their adjusted mortality risks showed overlapping CIs: 2.07 (95% CI, 1.69 to 2.53) and 2.84 (95% CI, 2.23 to 3.61), respectively. Conclusion LNR predicts survival after breast cancer more accurately than pN classification and should be considered as an alternative to pN staging.
Primary Sclerosing Cholangitis
Authors: Young-Mee Lee, Marshall M. Kaplan
Journal: New England Journal of Medicine (1995)

Primary sclerosing cholangitis, a chronic cholestatic liver disease of unknown cause, is characterized by ongoing inflammation, destruction, and fibrosis of intrahepatic and extrahepatic bile ducts.14 Over time, bile ducts become irregularly narrowed and obliterated, and small intrahepatic ducts disappear. Focal bile-duct dilatation proximal to areas of stricture produces a characteristic beaded appearance on cholangiography.5,6 Primary sclerosing cholangitis, although only about 1 percent as common as alcoholic liver disease,7,8 is the fourth leading indication for liver transplantation in adults in the United States.9 The disease progresses silently, but relentlessly, in most patients and leads to cirrhosis, portal hypertension, . . .
Androgens and Erythropoiesis
Authors: Nasrollah T. Shahidi
Journal: New England Journal of Medicine (1973)

SINCE early investigations exploring the role of sex hormones on the red cell, hemoglobin and hematocrit,1 , 2 numerous reports have now firmly established that androgens stimulate erythropoiesis. Administration of androgens to a variety of mammals and fowl has increased the reticulocyte count, hemoglobin and bone-marrow erythropoietic activity.3 4 5 Conversely, castration of the adult male in the same species results in a definite decrease in the peripheral red-cell count and hemoglobin concentration.3 , 5 6 7 8 The anemia in castrated male animals is restored to normal by administration of androgens.3 , 4 , 7 , 8 In man, repeated observations have shown that the adult male has higher hemoglobin, hematocrit and red-cell count . . .
Vesicoureteral Reflux
Authors: Gabrielle Williams, Jeffery T. Fletcher, Stephen I. Alexander, Jonathan C. Craig
Journal: Journal of the American Society of Nephrology (2008)

Vesicoureteral reflux (VUR), the retrograde flow of urine from the bladder toward the kidney, is common in young children. About 30% of children with urinary tract infections will be diagnosed with VUR after a voiding cystourethrogram. For most, VUR will resolve spontaneously; 20% to 30% will have further infections, but few will experience long-term renal sequelae. Developmentally, VUR arises from disruption of complex signaling pathways and cellular differentiation. These mechanisms are probably genetically programmed but may be influenced by environmental exposures. Phenotypic expression of VUR is variable, ranging from asymptomatic forms to severe renal parenchymal disease and end-stage disease. VUR is often familial but is genetically heterogeneous with variability in mode of inheritance and in which gene, or the number of genes, that are involved. Numerous genetic studies that explore associations with VUR are available. The relative utility of these for understanding the genetics of VUR is often limited because of small sample size, poor methodology, and a diverse spectrum of patients. Much, if not all, of the renal parenchymal damage associated with end-stage disease is likely to be congenital, which limits the opportunity for intervention to familial cases where risk prediction may be available. Management of children with VUR remains controversial because there is no strong supportive evidence that prophylactic antibiotics or surgical intervention improve outcomes. Furthermore, well-designed genetic epidemiological studies focusing on the severe end of the VUR phenotype may help define the causal pathway and identify modifiable or disease predictive factors.
<scp>FKBP12</scp> inhibits hepcidin expression by modulating <scp>BMP</scp> receptors interaction and ligand responsiveness in hepatocytes
Authors: Mariateresa Pettinato, Alessandro Dulja, Silvia Colucci, Valeria Furiosi, Franca Fette, Andrea U. Steinbicker, Martina U. Muckenthaler, Antonella Nai, Alessia Pagani, Laura Silvestri
Journal: American Journal of Hematology (2023)

Abstract The expression of the iron regulatory hormone hepcidin in hepatocytes is regulated by the BMP‐SMAD pathway through the type I receptors ALK2 and ALK3, the type II receptors ACVR2A and BMPR2, and the ligands BMP2 and BMP6. We previously identified the immunophilin FKBP12 as a new hepcidin inhibitor that acts by blocking ALK2. Both the physiologic ALK2 ligand BMP6 and the immunosuppressive drug Tacrolimus (TAC) displace FKBP12 from ALK2 and activate the signaling. However, the molecular mechanism whereby FKBP12 regulates BMP‐SMAD pathway activity and thus hepcidin expression remains unclear. Here, we show that FKBP12 acts by modulating BMP receptor interactions and ligand responsiveness. We first demonstrate that in primary murine hepatocytes TAC regulates hepcidin expression exclusively via FKBP12. Downregulation of the BMP receptors reveals that ALK2, to a lesser extent ALK3, and ACVR2A are required for hepcidin upregulation in response to both BMP6 and TAC. Mechanistically, TAC and BMP6 increase ALK2 homo‐oligomerization and ALK2–ALK3 hetero‐oligomerization and the interaction between ALK2 and the type II receptors. By acting on the same receptors, TAC and BMP6 cooperate in BMP pathway activation and hepcidin expression both in vitro and in vivo . Interestingly, the activation state of ALK3 modulates its interaction with FKBP12, which may explain the cell‐specific activity of FKBP12. Overall, our results identify the mechanism whereby FKBP12 regulates the BMP‐SMAD pathway and hepcidin expression in hepatocytes, and suggest that FKBP12–ALK2 interaction is a potential pharmacologic target in disorders caused by defective BMP‐SMAD signaling and characterized by low hepcidin and high BMP6 expression.
Meta-analysis of (single-cell method) benchmarks reveals the need for extensibility and interoperability
Authors: Anthony Sonrel, Almut Luetge, Charlotte Soneson, Izaskun Mallona, Pierre-Luc Germain, Sergey Knyazev, Jeroen Gilis, Reto Gerber, Ruth Seurinck, Dominique Paul, Emanuel Sonder, Helena L. Crowell, Imran Fanaswala, Ahmad Al-Ajami, Elyas Heidari, Stephan Schmeing, Stefan Milosavljevic, Yvan Saeys, Serghei Mangul, Mark D. Robinson
Journal: Genome biology (2023)

Computational methods represent the lifeblood of modern molecular biology. Benchmarking is important for all methods, but with a focus here on computational methods, benchmarking is critical to dissect important steps of analysis pipelines, formally assess performance across common situations as well as edge cases, and ultimately guide users on what tools to use. Benchmarking can also be important for community building and advancing methods in a principled way. We conducted a meta-analysis of recent single-cell benchmarks to summarize the scope, extensibility, and neutrality, as well as technical features and whether best practices in open data and reproducible research were followed. The results highlight that while benchmarks often make code available and are in principle reproducible, they remain difficult to extend, for example, as new methods and new ways to assess methods emerge. In addition, embracing containerization and workflow systems would enhance reusability of intermediate benchmarking results, thus also driving wider adoption.
Retained Metabolic Flexibility of the Failing Human Heart
Authors: William D. Watson, Peregrine G. Green, Andrew J.M. Lewis, Per Arvidsson, Giovanni Luigi De Maria, Håkan Arheden, Einar Heiberg, William T. Clarke, Christopher T. Rodgers, Ladislav Valkovič, Stefan Neubauer, Neil Herring, Oliver J. Rider
Journal: Circulation (2023)

The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation to increase oxygen efficiency of adenosine triphosphate production, with mixed results.